Autopsy studies have shown that middle-aged adults with Down's syndrome (DS) exhibit the neuropathological hallmarks of Alzheimer's disease (AD): amyloid senile plaques (SPs) and tau neurofibrillary tangles (NFTs). Clinical, neuroimaging, and genetic risk studies demonstrate similarities between demented DS patients and AD patients. Because of the increased risk and earlier age at onset for dementia in people with DS compared with the general population, DS has been proposed as a model for the study of AD, which afflicts an estimated 4.5 million people in the U.S. Our pilot positron emission tomography (PET) studies of adults with DS show lower brain glucose metabolic rates (measured with flurodeoxyglucose or [18F]FDG) in subjects with evidence of dementia, as well as a significant correlation between older age and higher signals for a novel measure of SPs and NFTs: [18F]FDDNP. Other PET studies show that [18F]FDDNP can distinguish AD from mild cognitive impairment and normal aging and that brain regions showing high signals demonstrate high postmortem concentrations of SPs and NFTs. To elucidate such observations, we propose performing clinical, neuropsychological, and PET imaging ([18]FDG and [18]FDDNP) studies on 72 people age 45 and older with DS (36 demented and 36 non-demented) and 36 age-matched controls. We will also perform magnetic resonance imaging scans to assist with image analysis, apolipoprotein E (APOE) typing for AD genetic risk determinations, and repeat assessments and scanning after 2 years to test the following hypotheses: (1) [18F]FDDNP signals will be greater in demented subjects with DS than in non-demented ones, who will have higher signals than controls;(2) Parietal and temporal metabolic rates measured by [18F]FDG will be higher in controls and non-demented people with DS compared with demented people with DS. (3) Within each diagnostic group, age will correlate with greater [18F]FDDNP signals. (4) At 2-year follow-up, [18F]FDDNP signals will increase in subjects with DS (both with and without dementia) compared to controls. Within the subject group with DS, we will explore differences in [18F]FDDNP signal change after 2 years according to the presence or absence of dementia at baseline. (5) After two years of follow-up, [18F]FDG signals will decrease in those subjects with DS showing evidence of decline (including developing dementia or worsening dementia) than in other groups. In addition to these hypotheses, we will explore the influence of APOE-4 on [18F]FDDNP and [18F]FDG signals in people with DS. Over the 5-year study period, we anticipate that approximately 6 older DS subjects will die, and we will explore correlations between neuropathological features of these cases and in vivo scanning and neuropsychological measures. This project will lead to a better understanding of the clinical and neuroimaging correlates of dementia in people with DS and provide the groundwork for future studies designed to improve early detection, diagnosis, and treatment of DS and AD, and thus improve the quality of life for millions of patients and their families afflicted by these conditions. PUBLIC HEALTH RELEVANCE: This project will lead to a better understanding of the clinical and neuroimaging correlates of dementia in people with Down's syndrome and provide the groundwork for future studies designed to improve early detection, diagnosis, and treatment of Down's syndrome and Alzheimer's disease. Given the many people suffering from these neurodegenerative diseases, the potential impact of this study will be considerable, possibly improving the quality of life for millions of patients and their families.